Cenicriviroc is the common name of (S,E)-8-(4-(2-Butoxyethoxy)phenyl)-1-(2-methylpropyl)-N-(4-(((1-propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydrobenzo[b]azocine-5-carboxamide (CVC), the chemical structure of which appears below.

Cenicriviroc binds to and inhibits the activity of the C—C chemokine receptor type 2 (CCR2) and C—C chemokine receptor type 5 (CCR5) receptors. These receptors not only play a role in entry of viruses such as Human Immunodeficiency Virus (HIV) into the cell, but also are important for the recruitment of immune cells to sites of injury. Inhibition of this receptor's activity may have an anti-inflammatory effect. Recently, the role that inflammation plays in the development of fibrosis has been examined. It has been shown that CCR2 and CCR5 may play a role in promoting hepatic fibrosis and that CVC has potential as a therapeutic agent in the treatment of hepatic fibrosis (International Publication No. WO 2015/143367).
The synthesis of CVC is described in U.S. Pat. No. 8,183,273; U.S. Publication No. 2005/0107606 and International Publication No. WO 2001/017947.
Cenicriviroc is weakly basic and poorly water-soluble. Several salts of CVC have been described. For example, U.S. Pat. No. 8,183,273; U.S. Publication No. 2005/107606 and International Publication No. WO 2016/105527 disclose preparations of a methanesulfonic acid salt of CVC (or CVC mesylate). However, none of these references describe a polymorphic form of the resulting CVC mesylate.
For instance, Example 10 of U.S. Pat. No. 8,183,273 discloses the preparation of “yellow crystals” of CVC mesylate. In the example, CVC (100 mg) was dissolved in ethyl acetate (4 mL) and methanesulfonic acid (9.31 μL in 2 mL of ethyl acetate) was added to the solution with vigorous stirring. After the addition was complete, the mixture was stirred overnight; the precipitated solids were collected by filtration; the collected solids were washed with ethyl acetate (5 mL) and dried under reduced pressure. The drying conditions (e.g., temperature, time and pressure) are not specified. The dried solids were recrystallized from 2-butanone (4 mL) to provide CVC mesylate as “yellow crystals.” Neither the recrystallization temperature profile nor the conditions used to dry the CVC mesylate are described. The “yellow crystals” exhibited a melting point of 145.5-147.5° C. However, no other polymorphic form characteristics of the product are disclosed.
Examples 15, 16 and 19 from U.S. Publication No. 2005/107606 describe the preparation of CVC mesylate. The CVC mesylate produced in Examples 15 and 19 is said to be in the form of “yellow crystals”. However, no other polymorphic form characteristics of the product are disclosed. Similarly, Example 16 is said to yield a “yellow powder”. However, no other polymorphic form characteristics of the product are disclosed.
In Example 15, crude CVC was dissolved in a mixture of acetonitrile (7 mL) and acetone (7 mL), and methanesulfonic acid (209 mg) and “seed crystals” were successively added to the solution. The resulting mixture was stirred for 100 minutes after which time acetonitrile/acetone (1:1, 5.0 mL) was added; the mixture was further stirred at room temperature overnight and then stirred under ice-cooling for 2.5 h; the precipitated solids were collected by filtration and washed with ice-cooled acetone (9 mL). The collected solids were dried at 40° C. under reduced pressure to obtain CVC mesylate as “yellow crystals.” Furthermore, the drying time for the “yellow crystals” is not described. Also, no other polymorphic form characteristics of the product are disclosed.
In Example 19, methanesulfonic acid (18.2 g) was added to a solution of crude CVC in a mixture of acetonitrile (720 mL) and ethyl acetate (720 mL), and the resulting mixture was stirred for 1 h after which time the precipitated solids were collected by filtration to provide CVC mesylate (141.8 g) as “yellow crystals.” No physical form characterization data is provided for the “yellow crystals.” Furthermore, the drying conditions (e.g., temperature, time and pressure) are not specified. Also, no other polymorphic form characteristics of the product are disclosed
In Example 16, methanesulfonic acid (0.65 mL) and “seed crystals” (80 mg) were successively added to a solution of crude CVC in methyl isobutyl ketone (15 mL). The resulting mixture was stirred for 16 h after which time methyl isobutyl ketone/ethyl acetate (1:1, 50 mL) was added. The mixture was stirred under ice-cooling for 2 h; the precipitated solids were collected by filtration; and the collected solids were dried at 40° C. under reduced pressure to obtain CVC mesylate (6.62 g) as “yellow powder.” The “yellow powder” was suspended in methyl isobutyl ketone (40 mL); the suspension was stirred for 16 hours; ethyl acetate (40 mL) was added to the suspension to provide a solution; the solution was stirred at room temperature for 1 hour; then stirred for 2 hours under ice-cooling and CVC mesylate was collected by filtration. The conditions used to dry CVC mesylate are not specified. The CVC mesylate produced in the example is described as a “yellow powder”. However, no other polymorphic form characteristics of the product are disclosed.
Example 4 of International Publication No. WO 2016/105527 describes the preparation of solid CVC mesylate. In the example, crude CVC was dissolved in a mixture of ethyl acetate and acetonitrile, then methanesulfonic acid (1.01 equivalent) and ethyl acetate were successively added to the solution. The resulting mixture was stirred for 30 minutes after which time the mixture was seeded with CVC mesylate and the mixture was stirred at 20° C. for 8 hours. The precipitated solids were collected by filtration and washed with chilled ethyl acetate. These “crude crystals” were dissolved in acetonitrile at 70° C. and the solution was cooled to 50-55° C. over 1 hour and seeded with CVC mesylate. The solution was stirred at 50-55° C. for 6 hours then cooled to 20° C. over 1 hour then stirred for 8 hours. The precipitated crystals were collected by filtration and washed twice with chilled acetonitrile to provide CVC mesylate. The reference describes the product as a “bright yellow solid”. However, no other polymorphic form characteristics of the product are disclosed.
M. Menning and S. Dalziel, Mol. Pharmaceutics (10) 4005-4015, 4006, (2013) disclose a monomesylate salt in a solid form as being a highly stable non-hygroscopic crystalline solid with a high melting point at 153° C. However, no other polymorphic form characteristics of the product are disclosed.
Thus, while the aforesaid described methods of making solid CVC mesylate, however the polymorphic characterization of the solids is not established. There is a need for CVC mesylate having high polymorphic purity and processes for making the same.
The present disclosure relates to polymorphic and stable amorphous forms of CVC mesylate, methods of their preparation, pharmaceutical compositions thereof and methods of their use.